Aberrant protein phosphorylation is now widely documented to be closely associated to the pathological aggregation of the microtubule-associated protein tau in a neurodegenerative process commonly referred to as neurofibrillary degeneration. The respective diseases, now encompassing about 22 common as well as very rare conditions, including Alzheimer's disease (AD), frontal lobe dementia (also known as frontotemporal degeneration (FTD)), corticobasal degeneration (CBD), Pick's disease (PiD), Parkinson with dementia (PDD), supranuclear palsy, argyrophilic grains disease (AGD) and a variety of lesser diseases not yet recognized by a commonly used name, all share the intracellular formation of neurofibrillary tangles (NFT) in various neuronal populations of the human brain functionally correlated with symptomatology. Irrespective of the clinical disease entity, neurofibrillary tangles are invariably composed ultrastructurally by either paired helical filaments (PHF), or less frequently by straight filaments (SF). Molecularly, paired helical filaments are exclusively composed of microtubule (MT) associated proteins tau in an abnormally hyperphosphorylated state never found in normal cell biology. In this pathological phosphorylation state, tau proteins are also unable to bind to microtubule and perform their normal physiological function of microtubule stabilization and neuron-specific organization of cytoskeleton and microtubule-dependent transport.
The dominant relevance of neurofibrillary degeneration in clinical diseases with neurofibrillary tangles, especially when collateral pathological features coexist, like in classical Alzheimer's disease, has long been conjectured but remained difficult to prove because tauopathies are found only in the human brain. The issue was unequivocally settled when certain tauopathies were found to be caused by mutations in tau, and these same mutations were able to precipitate lethal neurodegenerative phenotypes in tau-transgenic mice. Irrespective of whether paired helical filaments are produced with or without mutations in man, or with mutations in mice, the same type of pathological hyperphosphorylation of tau (PHF-tau) is invariably associated with their formation early in the process. This provides strong evidence that PHF-tau hyperphosphorylation is a common precursor pathway for neurofibrillary degeneration independent of etiology. Hence therapeutic agents interfering with this pathological phosphorylation biochemistry, e.g., by inhibition of appropriate kinases, are very likely to be effective in treating tauopathies.
Kinase inhibitors belonging to the group of glycosylated indolocarbazoles have received prominent attention in the last decade for inhibiting various kinases. The most prominent members of this class are the natural alkaloide products staurosporine and K252a. These and several other derivatives were investigated mostly for therapeutic uses in various cancer indications. WO 97/05140 describes a broad range of modified K252a derivatives, with a few compounds exemplified for therapeutic use in immunosuppression and proliferative diseases (cancer) by virtue of their PKC inhibitory activity.
So far, only one disclosure has been made about specific small molecule kinase inhibitors capable of inhibiting tau hyperphosphorylation in a cell model. Certain derivatives of synthetic analogues of K252a, which in contrast to most of the other compounds in the structural class described in the prior art, are not accessible through the natural product, showed useful potency and efficacy to prevent PHF-tau hyperphosphorylation [WO 00/01699]. These compounds, however, did not show a high degree of kinase specificity, but seemed to inhibit more than one kinase, and the synthesis could only provide for racemic compounds.
Moreover, the physicochemical properties of this series of compounds are very poor, resulting in the need to use non-GRAS (Generally Regarded As Safe under FDA guidelines) vehicles for compound application. In addition, even under specialized conditions of application, oral bioavailability for the prior art compounds usually does not exceed 10% in rats [WO 95/22331]. Possibly related to these unfortunate properties, half-lives in rats after i.v. application are unattractively short at about 1 h. Brain/plasma ratios determined in vivo as the concentration of the compound in brain over the concentration of the compound in plasma at a given time point are also poor, and deteriorate further when GRAS-vehicles are used, suggesting an unacceptable influence of vehicle on these parameters. Accordingly, chronic in vivo experiments for the inhibition of neurofibrillary pathology in authentic models, like transgenic mice carrying human pathogenic mutations of tau, cannot be conducted with such compounds.
Unfortunately, the restrictions of the above prior art compounds on pharmaceutical utility seem to be rather common to the indolocarbazole class of kinase inhibitors. Derivatives of the natural product K252a have also been reported to not exceed oral bioavailabilities of 10%. K252a itself showed a maximal oral bioavailability in rats of 13% and brain/plasma ratios well below 1.
These unfavorable physicochemical properties severely limit the utility of kinase inhibitors belonging to the group of glycosylated indolocarbazoles for pharmaceutical purposes, especially for the treatment of neurodegenerative and/or dementing illnesses where high brain/plasma ratios are required.
Accordingly, a need remains in the art for compounds belonging to the group of glycosylated indolocarbazoles that possess a high degree of kinase specificity and better solubility, oral bioavailability and blood-brain barrier penetration, allow a convenient synthetic access of the relevant pure enantiomers, and provide potent and efficacious inhibition of authentic PHF-tau hyperphosphorylation and inhibition of neurofibrillary degeneration.